Exposure to ambient particulate matter (PM) air pollution accounts up to 3.1 years of life lost in the most compared with the least polluted US cities. The mortality associated with acute exposure to ambient PM is largely due to ischemic cardiovascular events. While the mechanisms linking PM exposure with acute cardiovascular events are not fully understood, human and animal data increasingly suggest that PM-induced alterations in hemostasis resulting from lung inflammation and activation of the sympathetic nervous system play causal roles. In the first cycle of this award, we reported that acute exposure to PM causes lung macrophages to release interleukin-6 (IL-6), which accelerates arterial thrombosis in mice, a finding supported by human studies. In our preliminary data we observed that PM-induced opening of Calcium-Release Activated Calcium (CRAC) channels and mitochondrial reactive oxygen species (ROS) play a critical role in PM-induced IL-6 release. We also observed that mice exposed to inhaled PM had increased lung and systemic levels of epinephrine and norepinephrine, directly confirming data from human exposure studies suggesting that PM exposure activates the sympathetic nervous system. Surprisingly, the administration of a ?-blocker or genetic loss of the ?2-adrenergic receptor (?2AR) inhibited the PM-induced release of IL-6 and the subsequent prothrombotic state. Conversely, inhalation of a long acting ?2-agonist (formoterol) augmented the PM-induced release of IL-6 and the resulting prothrombotic state. These results suggest that activation of the sympathetic nervous system in response to PM augments the release of IL-6 from alveolar macrophages and contributes to resulting prothrombotic state. In the current proposal, we have developed 3 specific aims to test the hypothesis that stimulation of the ?2AR by locally derived catecholamines augments the PM-induced release of IL-6 from alveolar macrophages and the resulting prothrombotic state through CRAC channel and ROS- mediated augmentation of cAMP production. In aim 1, we will determine whether the activation of alveolar macrophage ?2ARs is required for the PM-induced release of IL-6 and the resulting prothrombotic state. In aim 2, we will determine whether PM-induced opening of CRAC channels and generation of mitochondrial ROS amplify the ?2AR/cAMP-dependent augmentation of IL-6 release. In aim 3, we will determine whether autocrine catecholamine signaling in alveolar macrophages augments PM-induced IL-6 release and the resulting prothrombotic state. Our findings provide a novel mechanistic paradigm linking PM-induced lung inflammation and activation of the sympathetic nervous system with an increased risk of thrombosis leading to ischemic cardiovascular events. In addition, our observation that the administration of a widely used inhaled long acting ?2AR agonist augments PM-induced IL-6 release and thrombosis provides a potential mechanism to explain the increasing body of evidence showing that the use of inhaled ?2-agonists is associated with increased mortality in patients with COPD and asthma.